GABAB receptor modulation of synaptic function

Abstract

Neuromodulators have complex effects on both the presynaptic release and postsynaptic detection of neurotransmitters. Here we describe recent advances in our understanding of synaptic modulation by metabotropic GABAB receptors. By inhibiting multivesicular release from the presynaptic terminal, these receptors decrease the synaptic glutamate signal. GABAB receptors also inhibit the Ca2+ permeability of NMDA receptors to decrease Ca2+ signals in postsynaptic spines. These new findings highlight the importance of GABAB receptors in regulating many aspects of synaptic transmission. They also point to novel questions about the spatiotemporal dynamics and sources of synaptic modulation in the brain.

Figure 1. Post-synaptic intracellular GABA_B-R signaling

GABA binding to GABA_B-R heterodimers releases Gβγ subunits that locally diffuse to open K⁺ channels and close Ca²⁺ channels. In addition, released Gα_i/Gα_o subunits inhibit adenylyl cyclase (AC), which constitutively produces cAMP to activate PKA, with potentially many downstream targets including NMDA-Rs.

Figure 2. Modulation of postsynaptic NMDA-R Ca signals

A, Left, Two-photon image of dendrite and spines, showing uncaging location (asterisk) and line-scan position (dashed yellow line). Right, Line-scans (top) show a change in green Ca²⁺ signal after two-photon uncaging, quantified (bottom) before (red) and after (black) wash-in of the NMDA-R antagonist CPP. B, Average NMDA-R currents (left) and Ca²⁺ signals (right) before (red) and after wash-in of the GABA_B-R agonist baclofen (black) (adapted from Chalifoux & Carter, 2010).